A-norsteroids



United States Patent 3,468,955 A-NORSTEROIDS Seymour ll). Levine, North Brunswick, and Patrick A. Diassi, Westfield, N..l., assignors, by mesne assignments, to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Original application Mar. 16, 1965, Ser. No. 440,311, new Patent No. 3,330,851, dated July 11, 1967. Divided and this application Mar. 9, 1967, Ser. No. 621,755

Int. Cl. C07c 171/06, 173/00; A611; 17/06 US. Cl. 260586 2 Claims ABSTRACT OF THE DISCLOSURE This invention relates to new final products that are steroids of the A-norandrostane series of the Formula I given below and to new Z-ketal derivatives thereof of the Formula II given below which are useful as intermediates in preparing said final products. The intermediates are l7-ketone substances that are converted to the final product by reacting with a Grignard reagent or similar compound. The final products are physiologically active compounds that possess fertility inhibiting activity.

This application is a division of our application, Ser. N0. 440,311, filed Mar. 16, 1965, now Patent No. 3,330,- 851.

This invention relates to new steroidal compounds and, more particularly, to new steroids of the A-norandrostane series, new intermediates useful in the preparation of the same, and processes for preparing the same.

The new final products of this invention are of the Formula I:

wherein Y is fi-hydrogen or ,fi-cyano; R is hydroxy or acyloxy; and R is vinyl, ethynyl, halo substituted vinyl, trifiuoromethyl substituted vinyl, halo substituted ethynyl and trifluoromethyl substituted ethyuyl. Among the suitable acyloxys may be mentioned the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric, hexanoic and enanthic acid), the lower alkenoic acids, the cycloalkane carboxylic acids, the cycloalkene carboxylic acids, the monocyclic aromatic carboxylic acids (e.g., benzoic acid), and the monocyclic aryl lower alkanoic acids (e.g., phenacetic and ,3- phenylpropionic acid). Among the suitable halogen substituted vinyls may be mentioned perhalovinyls, such as trifiuorovinyl, trichlorovinyl, 1,2-difluoro-2-chlorovinyl and l,2-difluoro-2-brornovinyl; the dihalovinyls, such as l,2difiuorovinyl, 2,2-difiuorovinyl, l-chloro-2-fiuorovinyl, l-bromo-Z-fiuorovinyl, and 1,2-dichlorovinyl; and the monohalovinyls, such as l-fluorovinyl, Z-fluorovinyl, 1- chlorovinyl, 2-chlorovinyl, and l-bromovinyl. Among the suitable halogen substituted ethynyls may be mentioned fiuoroethynyl, chloroethynyl and bromoethynyl.

The final products of this invention are physiologically active compounds that possess fertility inhibiting activity. Hence, they may be administered orally or parenterally in lieu of known anti-fertility agents, such as progestagens and estrogens for control of conception, the dose being adjusted for the activity of the particular compound.

The compounds of this invention are prepared by interacting a compound of the Formula II:

wherein Y is as hereinbefore defined and R" is keto or ketal, with a compound of the formula: R'X, wherein R is as hereinbefore defined, and X is an activating group such as magnesium bromide, lithium or a complex thereof (e.g., a lithium ethylenediamine complex). When Y is cyano, a Z-ketal (R" is ketal) must be used. When Y is hydrogen, either a Z-ketal or 2-ketone may be used as the reactant. Although any ketal may be used, the preferred ketals are those with alkanediols, such as ethylene glycol and propylene glycol. To complete the reaction,

' water is then added, thereby yielding products of the wherein Y, R and R" are as hereinbefore defined.

If the compound of Formula III formed contains a 2- ketal group, it may be hydrolyzed, by treatment with an aqueous solution of a strong acid, such as p-toluenesulfonic acid, to yield the corresponding 2-keto derivative. If a 17-ester is desired as the final product, the compound of Formula III, in its free Z-keto form, is reacted with the acyl chloride or acid anhydride of the desired acid, preferably one of the acids mentioned hereinbefore, to yield the l7-ester.

In those instances where ketals of Formula II are used, they may be prepared by first treating either Sfi-cyano-A- nortestosterone (prepared as described in US. patent application, Ser. No. 355,913, filed Mar. 30, 1964, now Patent No. 3,350,964) or Sp-A-norandrostane-Z-one 175- 01 with a ketalizing agent, such as ethylene glycol or propylene glycol, in the presence of a strong acid, such as p-toluenesulfonic acid, to yield the corresponding Z-ketal derivative; and then oxidizing such derivative, as by treatment with chromium trioxide, to yield the corresponding l7-keto derivative.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 17a-ethynyl-Sfi-cyano-A-norandrostane-2-one-1718-01 Z-ethylene ketal (III) (a) Preparation of 5B-cyano-A-norandrostane-2-one- 175-01 Z-ethylene ketal l7-acetate.A mixture of mg. of S/S-cyano-A-nortestosterone and 7 mg. of p-toluenesulfonic acid is stirred and refluxed in 40 ml. of benzene and 3 ml. of ethylene glycol for one day and the water removed by a calcium carbide trap. The reaction mixture is diluted with Water and the benzene layer is separated. The aqueous layer is extracted with additional benzene.

solution and evaporated to give a residue which is acetylated by refluxing in 2 ml. of acetic anhydride containing 0.2 ml. of pyridine for one hour. The reaction mixture is poured into ice-water and extracted with chloroform. The chloroform extracts are washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using a mixture of chloroform and hexane (1:2) as the developing solvent gives a major band at about Rf 0.35 which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from isopropyl etherhexane gives about 75 mg. of 5,8-cyano-A- norandrostane-Z-one-175-01 Z-ethylene ketal 17-acetate, M.P. about 175177. The analytical sample is prepared by recrystallization from isopropyl etherhexane, M.P. about 1825-1835"; +3 (EtOH); x 4.50 and 5.77u; TSKCHM 9.20 (s., 18-Me), 8.78 (s., l9-Me), 7.97 (s., 17-acetate), and 6.13 (m., ketal methylenes).

Analysis.Calcd. for C H O N (387.50): C, 71.29; H, 8.58; N, 3.61. Found: C, 71.28; H, 8.59; N, 3.50.

(b) Preparation of SB-cyano-A-norandrstane-2-one- 175-01 2-ethylene ketaL-(i) A solution of 100 mg. of SB-cyano-A-norandrostane-2-one-175-01 2-ethylene ketal 17-acetate in 1 ml. of 10% aqueous potassium carbonate solution and 10 ml. of methanol is stirred at room temperature for 18.5 hours. The reaction mixture is diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using a mixture of chloroform and hexane (2:1) as the developing solvent gives a major band which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystallization of the residue from isopropyl ether gives about 40 mg. of 5,8-cyano-A-norandrostane- 2-one-17fl-ol 2-ethylene ketal, M.P. about 172l74. The analytical sample is prepared by recrystallization from isopropyl ether, M.P. about 175.5-176.5, [u] +6 (EtOH); A 2.85 and 4.50/1.; TSKCHBH 9.26 (s., 18-Me), 8.79 (s., 19-Me), 6.12 (m., ketal methylenes) and 6.38 (m., 17-H).

Analysis.-Calcd. for C H O N (345.47): C, 73.00; H, 9.05. Found: C, 72.92; H, 9.01. 7 (ii) Ketalization of 5B-cyano-A-nortestosterone as de scribed in Step (i) of this example gives rise to S S-cyano- A-norandrdstane-Z-one-178-01 2-ethylene ketal.

(0) Preparation of 5fi-cyano A norandrostane-2,l7- dione 2-ethylene ketal.-A solution of 50 mg. of 56- cyano-A-norandrostane-2-one-1713-01 Z-ethylene ketal in 2 ml. of acetone is treated dropwise with stirring with an equivalent amount of chromium trioxidesulfuric acid. The reaction mixture is treated with one drop of pyridine, filtered and diluted with water. The aqueous phase is extracted with ether. The ether extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from chloroform-isopropyl ether gives about 27 mg. of 5B- cyano-A-norandrostane-2,17-dione -2-ethylene ketal, M.P. about 212.5-213.5. The analytical sample is prepared by recrystallization from chloroform-isopropyl ether, M.P. about 2135-2145", +73 (EtOH); A 4.50 and 5.78 1; TSKCH3 4 9.12 (s., 18-Me), 8.76 (s., 19-Me) and 6.13 (m., ketal methylenes).

Analysis.-Calcd. for C H O N (343.45): C, 73.43; H, 8.51; N, 4.08. Found: C, 73.40; H, 8.52; N, 4.32.

(d) Preparation of 17a-ethynyl-5fi-cyano A norandrostane-2-one-17/3-ol 2-ethylene ketal.-A mixture of 200 mg. of Sit-cyano-A-norandrostane-2,17-dione 2-ethylene ketal rod 100 mg. of lithium acetylide ethylenediamine complex in ml. of benzene and 10 ml. of tetrahydrofuran under an atmosphere of helium is slowly warmed to 45 over a one hour period and maintained at this temperature for 6 additional hours. The reaction mixture is treated with 5 ml. of water and refluxed for 4 one hour, diluted with water and extracted with chloroform. The chloroform extracts are "washed with 8% salt solution, dried over sodium sulfate and evaportaed to dryness. Crystallization of the residue from methanol gives 61 mg. of 17a-ethynyl-5/3-cyano-A-norandrostane- 2-one-17 6-ol 2-ethylene ketal, M.P. about 262264. The analytical sample is prepared by recrystallization from methanol-isopropyl ether, M.P. about 269270, 32 (EtOH l-l drop pyridine); A 2.92, 3.08 and 4.50 1..

Analysis.-Calcd. for C H O N (369.49): C, 74.76; H, 8.46. Found: C, 74.65,; H, 8.57. 4

EXAMPLE 2 17a-ethynyl-5/3-cyano-A-norandrostane-Z-one-175-01 A mixture of 220 mg. of 17ot-ethynyl-5fl-cyano-A- norandrostane-2-one-175-01 2-ethylene ketal and 25 mg. of p-toluene'sulfonic acid in 2 ml. of water and 20 ml. of acetone is refluxed for 22 hours, diluted with water and the acetone evaporated. The aqueous phase is extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness. Plate chromatography of the residue on neutral alumina (Activity V) using chloroform as the developing solvent gives a major band which is detectable with iodine. Elution with ethyl acetate, evaporation, and crystatllization of the residue from ethyl acetate-isopropyl ether gives 112 mg. of l7a-ethynyl-5B- cyano-A-norandrostane-2-one-17- 8-01, M.P. about 174- 176. The analytical sample is prepared by recrystallization from ethylacetate-petroleum ether (B.P. 3075), M.P. about 1815-1825", [04],; -124 (EtOH); A 2.93, 3.05, 4.50 and 5.72,, TSKCHQM 9.13 (s., 19-Me), 8.61 (s., l9-Me), and 7.42 (s., 17a-ethynyl-H).

Analysis.Calcd. for C H O N (325.43): C, 77.50; H, 8.36. Found: C, 77.59; H, 8.42.

EXAMPLE 3 17 a-ethynyI-S B-cyano-A-norandrostane-2-one- 1713-01 acetate A solution of 0.0033 ml. of perchloric acid in 0.3 ml. of acetic anhydride is added to 500 mg. of 17a-ethynyl- 5p cyano A norandrostane-Z-one-1718-01 in 10 ml. of acetic anhydride. The reaction mixture is stirred at room temperature for 30 minutes and then poured into icewater and extracted with chloroform. The chloroform extracts are washed with a saturated sodium bicarbonate solution, 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17a-ethynyl-5fi-cyano-A- norandrostane-Z-one-17,8-01 acetate.

Similarly, by substituting any other acyl chloride or acid anhydride-for the acetic anhydride in the procedure of Example 3, the corresponding 17-ester is formed. Thus, propionic anhydride and benzoyl chloride yield the propionate and benzoate, respectively.

I EXAMPLE 4 A solution of mg. of Sfi-cyanmA-norandrostane- 2,17-dione Z-ethylene ketal in 15 ml. of tetrahydrofuran is treated with an excess of trifluoropropynylmagnesium bromide (prepared from ethyl magnesium bromide and excess trifluoropropyne in tetrahydrofuran solution). The reaction mixture is refluxed for 6 hours, cooled, and then treated with a saturated ammonium chloride solution and the organic layer separated. The aqueous layer is extracted with chloroform. The combined organic fractions are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give 17a-trifluoropropynyl-Sfi-cyano A-norandrostane-Z-one-17,8-01 2-ethylene-ketal.

EXAMPLE 5 17a-and 17fi-chloroethynyl-Sfi-cyano-A-norandrostane-2-one-l7-ols Z-ethylene ketal A solution of 250 mg. of 55-cyano-A-norandrostane- 2,17-dione 2ethylene ketal in 20 ml. of ether is added dropwise to an excess of chloroethynyllithium (prepared from cis-1,2-dichloroethylene and methyllithium in ether) solution over a minute period. The reaction mixture is left at room temperature for 2.5 hours and treated with ice-water and additional ether. The ether layer is separated, washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give a mixture of 1711- and 17/3-chloroethynyl 5B cyano-A-norandrostane-2-one-17-ols 2-ethylene ketal which are separable by chromatography on neutral alumina (Activity V).

EXAMPLE 6 17a-trifluorovinyl-5,8-cyano-A-norandrostane-2-one- 17,8-01 2-ethylene ketal A solution of 300 mg. of 5,8-cyano-A-norandrostane- 2,17-dione 2-ethylene ketal in 25 ml. of tetrahydrofuran is treated with an excess of trifiuorovinylmagnesium bromide (prepared from magnesium and trifluorobromoethylene in tetrahydrofuran solution). The reaction mixture is refluxed for 6 hours, cooled, and then treated with a saturated ammonium chloride solution and the organic layer separated. The aqueous layer is extracted with chloroform. The combined organic fractions are washed with 8% salt solution, dried over sodium sulfate and evaporated to dryness to give l7a-trifluorovinyl-5flcyano-A-norandrostane-Z-one-173-01 Z-ethylene ketal.

Similarly, by substituting the indicated magnesium bromide for the trifiuorovinylmagnesium bromide in the procedure of Example 6, the indicated 17a-R'-5B-cyano- A-norandrostane-Z-one-175-01 Z-ethylene ketal, is formed:

Example Reactant Product R is- 7 B-Vinylmagnesium bromide Vinyl.

8 fl-Chlorovinylmagnesium B-Chlorovinyl.

bromide.

9 a, B-Dichlorovinylmagnesium a, B-Dichlorovinyl.

bromide.

10 a, B-Difluorovinylmagnesium a, B-Difiuorovinyl.

bromide.

EXAMPLE ll Example Reactant R is: Product R is:

12 17a-chloroethynyl l7a-chloroethynyl. l3 175-ch10roethynyl. 175-chloroethynyl. 14 17a,trifiuorovinyl 17a-trifiuorovinyl.

15- l7a-B-chlorovinyL. 17a-1S-ehlorovinyl.

16- 17zx-a, B-dichlorovinyl- 17am, tl-dichlorovinyl. 17 17am, B-difiuorovinyl 1701-01, B-difluorovinyl.

EXAMPLE 18 17a-trifluoropropynyl-5B-cyano-A-norandrostane- 2-one-17p-ol acetate Following the procedure of Example 3, but substituting an equivalent amount of 17a-trifluoropropynyl-Slit-cyano- A-norandrostane-2-one-175-01 for the 17a-ethynyl-5flcyano-A-norandrostane-2-one-17 8-01, there is obtained 17oz trifiuoropropynyl-5,3-cyano-A-norandrostane-2-one- -01 acetate.

EXAMPLE 19 17a-ethynyl-5B-A-norandrostane-Z-one-175-01 Following the procedure in Example 1, step (d), but substituting SB-A-norandrostane-Z,17-dione for 5,8-cyano- A-norandrostane-Z,17-dione Z-ethylene ketal, there is obtained 17a-ethynyl 5,8 A norandrostane-Lone-17-01, A 2.91, 3.03 and 5.78,u.

EXAMPLE 2O l7a-trifluoropropynyl-Sfi-A-norandrostane- 2-one- 1719-01 Following the procedure in Example 4, but substituting Sfi-A-norandrostane-Z,17-dione for SB-cyano-A-norandrostane-2,17-dione Z-ethylene ketal, there is obtained l7a-trifiuoropropynyl-SB-A-norandrostane 2 one-17B- ol.

EXAMPLE 21 17aand 17 3-chloroethynyl-5}8-A-norandrostane- 2-one-l7-ols Following the procedure in Example 5, but substituting 5fi-A-norandrostane-2,17-dione for 5 3-cyano-A-norandrostane-2,17-dione Z-ethylene ketal, there is obtained a mixture of 17ocand 17,8-chloroethylnyl-SB-A-norandrostane- 2-one-17-ols.

EXAMPLE 22 l7a-trifiuorovinyl-SE-A-norandrostaue-Z-one-17 6-01 Following the procedure in Example 6, but substituting SB-A-norandrostane-Z,17-dione for 5/8-cyano-A-norandrostane-2,l7-dione Z-ethylene ketal, there is obtained 17atrifiuorovinyl-Sfl-A-norandrostane-Z-one-175-01.

EXAMPLE 23 17 a-trifiouoropropenyl-S B-A-norandrostane-Z-one-175-01 Hydrogenation of 17a-trifiuoropropynyl-SB-A-norandrostane-2-one-17B-ol at 45 psi. with Lindlar catalyst gives l7oc-trifiuoropropenyl-SB-A-norandrostane-2-one.

EXAMPLE 24 l7a-ethynyl-5,B-A-norandrostane-2-one-175-01 acetate wherein R is selected from the group consisting of hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, and R is selected from the group consisting of vinyl, ethynyl, halo substituted vinyl, trifiuoromethyl substituted vinyl, halo substituted ethynyl and trifluoromethyl substituted ethynyl.

2. A compound of claim 1 having the name 17aethynyl-Sfl-A-norandrostane-Z-one-175-01.

Referenes Cited FOREIGN PATENTS 629,538 10/1963 Belgium.

OTHER REFERENCES Pincus et al., Steroids, pp. 658 and 659 (July-December 1964).

LEON ZITVER, Primary Examiner 10 M. M. JACOB, Assistant Examiner 

